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Published in: Journal of Neuro-Oncology 2/2019

Open Access 01-01-2019 | Clinical Study

Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial

Authors: S. A. Toms, C. Y. Kim, G. Nicholas, Z. Ram

Published in: Journal of Neuro-Oncology | Issue 2/2019

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Abstract

Background

Tumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary for compliance with improved clinical outcomes.

Methods

Compliance was assessed by usage data from the NovoTTF-100A device and calculated as percentage per month of TTFields delivery. TTFields/TMZ patients were segregated into subgroups by percent monthly compliance. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance on PFS and OS.

Results

A threshold value of 50% compliance with TTFields/TMZ improved PFS (HR 0.70, 95% CI 0.47–1.05) and OS (HR 0.67, 95% CI 0.45–0.99) versus TMZ alone with improved outcome as compliance increased. At compliance > 90%, median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival rate was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p = 0.031; OS at compliance ≥ 75% vs. < 75%).

Conclusion

A compliance threshold of 50% with TTFields/TMZ correlated with significantly improved OS and PFS versus TMZ alone. Patients with compliance > 90% showed extended median and 5-year survival rates. Increased compliance with TTFields therapy is independently prognostic for improved survival in glioblastoma.
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Literature
1.
go back to reference Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2017) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro-oncology 19:v1–v88CrossRefPubMedPubMedCentral Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2017) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro-oncology 19:v1–v88CrossRefPubMedPubMedCentral
2.
go back to reference Koshy M, Villano JL, Dolecek TA, Howard A, Mahmood U, Chmura SJ, Weichselbaum RR, McCarthy BJ (2012) Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neuro-oncol 107:207–212CrossRef Koshy M, Villano JL, Dolecek TA, Howard A, Mahmood U, Chmura SJ, Weichselbaum RR, McCarthy BJ (2012) Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neuro-oncol 107:207–212CrossRef
3.
go back to reference Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRef Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRef
4.
go back to reference Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD (2018) Tumor-treating fields: a fourth modality in cancer treatment. Clin Cancer Res 24:266–275CrossRefPubMed Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD (2018) Tumor-treating fields: a fourth modality in cancer treatment. Clin Cancer Res 24:266–275CrossRefPubMed
5.
6.
go back to reference Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y (2004) Disruption of cancer cell replication by alternating electric fields. Cancer Res 64:3288–3295CrossRefPubMed Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y (2004) Disruption of cancer cell replication by alternating electric fields. Cancer Res 64:3288–3295CrossRefPubMed
7.
go back to reference Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y (2007) Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA 104:10152–10157CrossRefPubMed Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y (2007) Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA 104:10152–10157CrossRefPubMed
8.
go back to reference Kirson ED, Schneiderman RS, Dbaly V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y (2009) Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys 9:1CrossRefPubMedPubMedCentral Kirson ED, Schneiderman RS, Dbaly V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y (2009) Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys 9:1CrossRefPubMedPubMedCentral
9.
go back to reference Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y (2014) Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol 41(Suppl 6):S35–S41CrossRefPubMed Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y (2014) Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol 41(Suppl 6):S35–S41CrossRefPubMed
10.
go back to reference Gera N, Yang A, Holtzman TS, Lee SX, Wong ET, Swanson KD (2015) Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS ONE 10:e0125269CrossRefPubMedPubMedCentral Gera N, Yang A, Holtzman TS, Lee SX, Wong ET, Swanson KD (2015) Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS ONE 10:e0125269CrossRefPubMedPubMedCentral
11.
12.
go back to reference Porat Y, Shteingauz A, Giladi M, Schneiderman RS, Voloshin T, Munster M, Blat R, Kirson ED, Weinberg U, Palti Y (2017) Abstract 3315: cancer cells upregulate autophagy as a survival mechanism in response to tumor treating fields (TTFields). Cancer Res 77:3315–3315CrossRef Porat Y, Shteingauz A, Giladi M, Schneiderman RS, Voloshin T, Munster M, Blat R, Kirson ED, Weinberg U, Palti Y (2017) Abstract 3315: cancer cells upregulate autophagy as a survival mechanism in response to tumor treating fields (TTFields). Cancer Res 77:3315–3315CrossRef
14.
go back to reference Karanam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD (2017) Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis 8:e2711CrossRefPubMedPubMedCentral Karanam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD (2017) Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis 8:e2711CrossRefPubMedPubMedCentral
15.
go back to reference Kim EH, Song HS, Yoo SH, Yoon M (2016) Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis. Oncotarget 7:65125–65136PubMedPubMedCentral Kim EH, Song HS, Yoo SH, Yoon M (2016) Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis. Oncotarget 7:65125–65136PubMedPubMedCentral
16.
go back to reference Giladi M, Voloshin T, Shteingauz A, Munster M, Blat R, Porat Y, Schneiderman RS, Cahal S, Itzhaki A, Kirson E, Weinberg U, Palti Y (2016) Alternating electric fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. J Immunol 196:75.26 Giladi M, Voloshin T, Shteingauz A, Munster M, Blat R, Porat Y, Schneiderman RS, Cahal S, Itzhaki A, Kirson E, Weinberg U, Palti Y (2016) Alternating electric fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. J Immunol 196:75.26
17.
go back to reference Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y (2015) Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci Rep 5:18046CrossRefPubMedPubMedCentral Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y (2015) Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci Rep 5:18046CrossRefPubMedPubMedCentral
18.
go back to reference Giladi M, Munster M, Schneiderman RS, Voloshin T, Porat Y, Blat R, Zielinska-Chomej K, Haag P, Bomzon Z, Kirson ED, Weinberg U, Viktorsson K, Lewensohn R, Palti Y (2017) Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells. Radiat Oncol (London) 12:206CrossRef Giladi M, Munster M, Schneiderman RS, Voloshin T, Porat Y, Blat R, Zielinska-Chomej K, Haag P, Bomzon Z, Kirson ED, Weinberg U, Viktorsson K, Lewensohn R, Palti Y (2017) Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells. Radiat Oncol (London) 12:206CrossRef
19.
go back to reference Kim EH, Kim YH, Song HS, Jeong YK, Lee JY, Sung J, Yoo SH, Yoon M (2016) Biological effect of an alternating electric field on cell proliferation and synergistic antimitotic effect in combination with ionizing radiation. Oncotarget 7:62267–62279PubMedPubMedCentral Kim EH, Kim YH, Song HS, Jeong YK, Lee JY, Sung J, Yoo SH, Yoon M (2016) Biological effect of an alternating electric field on cell proliferation and synergistic antimitotic effect in combination with ionizing radiation. Oncotarget 7:62267–62279PubMedPubMedCentral
20.
go back to reference Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH (2012) NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer (Oxford, England: 1990) 48:2192–2202CrossRef Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH (2012) NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer (Oxford, England: 1990) 48:2192–2202CrossRef
22.
go back to reference Vymazal J, Wong ET (2014) Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin Oncol 41(Suppl 6):S14–S24CrossRefPubMed Vymazal J, Wong ET (2014) Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin Oncol 41(Suppl 6):S14–S24CrossRefPubMed
23.
go back to reference Mrugala MM, Engelhard HH, Dinh Tran D, Kew Y, Cavaliere R, Villano JL, Annenelie Bota D, Rudnick J, Love Sumrall A, Zhu JJ, Butowski N (2014) Clinical practice experience with NovoTTF-100A system for glioblastoma: the patient registry dataset (PRiDe). Semin Oncol 41 Suppl 6: S4–S13 Mrugala MM, Engelhard HH, Dinh Tran D, Kew Y, Cavaliere R, Villano JL, Annenelie Bota D, Rudnick J, Love Sumrall A, Zhu JJ, Butowski N (2014) Clinical practice experience with NovoTTF-100A system for glioblastoma: the patient registry dataset (PRiDe). Semin Oncol 41 Suppl 6: S4–S13
24.
go back to reference Stupp R, Taillibert S, Kanner A et al (2017) Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316CrossRefPubMedPubMedCentral Stupp R, Taillibert S, Kanner A et al (2017) Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316CrossRefPubMedPubMedCentral
25.
go back to reference Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 314:2535–2543CrossRefPubMed Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 314:2535–2543CrossRefPubMed
26.
go back to reference Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R (2018) Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial. JAMA Oncol. 4:495–504CrossRefPubMedPubMedCentral Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R (2018) Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial. JAMA Oncol. 4:495–504CrossRefPubMedPubMedCentral
28.
go back to reference Murphy J, Bowers ME, Barron L (2016) Optune(R): practical nursing applications. Clin J Oncol Nurs 20:S14–S19CrossRefPubMed Murphy J, Bowers ME, Barron L (2016) Optune(R): practical nursing applications. Clin J Oncol Nurs 20:S14–S19CrossRefPubMed
29.
go back to reference McCue DA, Lohr LK, Pick AM (2014) Improving adherence to oral cancer therapy in clinical practice. Pharmacotherapy 34:481–494CrossRefPubMed McCue DA, Lohr LK, Pick AM (2014) Improving adherence to oral cancer therapy in clinical practice. Pharmacotherapy 34:481–494CrossRefPubMed
30.
go back to reference Lacouture ME, Davis ME, Elzinga G, Butowski N, Tran D, Villano JL, DiMeglio L, Davies AM, Wong ET (2014) Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma. Semin Oncol 41(Suppl 4):S1–S14CrossRefPubMed Lacouture ME, Davis ME, Elzinga G, Butowski N, Tran D, Villano JL, DiMeglio L, Davies AM, Wong ET (2014) Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma. Semin Oncol 41(Suppl 4):S1–S14CrossRefPubMed
31.
go back to reference Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM (2007) Statistics in medicine—reporting of subgroup analyses in clinical trials. N Engl J Med 357:2189–2194CrossRefPubMed Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM (2007) Statistics in medicine—reporting of subgroup analyses in clinical trials. N Engl J Med 357:2189–2194CrossRefPubMed
32.
go back to reference Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, Heth JA, Salacz M, Taylor S, D’Andre SD, Iwamoto FM, Dropcho EJ, Moshel YA, Walter KA, Pillainayagam CP, Aiken R, Chaudhary R, Goldlust SA, Bota DA, Duic P, Grewal J, Elinzano H, Toms SA, Lillehei KO, Mikkelsen T, Walbert T, Abram SR, Brenner AJ, Brem S, Ewend MG, Khagi S, Portnow J, Kim LJ, Loudon WG, Thompson RC, Avigan DE, Fink KL, Geoffroy FJ, Lindhorst S, Lutzky J, Sloan AE, Schackert G, Krex D, Meisel HJ, Wu J, Davis RP, Duma C, Etame AB, Mathieu D, Kesari S, Piccioni D, Westphal M, Baskin DS, New PZ, Lacroix M, May SA, Pluard TJ, Tse V, Green RM, Villano JL, Pearlman M, Petrecca K, Schulder M, Taylor LP, Maida AE, Prins RM, Cloughesy TF, Mulholland P, Bosch ML (2018) First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 16:142CrossRefPubMedPubMedCentral Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, Heth JA, Salacz M, Taylor S, D’Andre SD, Iwamoto FM, Dropcho EJ, Moshel YA, Walter KA, Pillainayagam CP, Aiken R, Chaudhary R, Goldlust SA, Bota DA, Duic P, Grewal J, Elinzano H, Toms SA, Lillehei KO, Mikkelsen T, Walbert T, Abram SR, Brenner AJ, Brem S, Ewend MG, Khagi S, Portnow J, Kim LJ, Loudon WG, Thompson RC, Avigan DE, Fink KL, Geoffroy FJ, Lindhorst S, Lutzky J, Sloan AE, Schackert G, Krex D, Meisel HJ, Wu J, Davis RP, Duma C, Etame AB, Mathieu D, Kesari S, Piccioni D, Westphal M, Baskin DS, New PZ, Lacroix M, May SA, Pluard TJ, Tse V, Green RM, Villano JL, Pearlman M, Petrecca K, Schulder M, Taylor LP, Maida AE, Prins RM, Cloughesy TF, Mulholland P, Bosch ML (2018) First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 16:142CrossRefPubMedPubMedCentral
Metadata
Title
Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial
Authors
S. A. Toms
C. Y. Kim
G. Nicholas
Z. Ram
Publication date
01-01-2019
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 2/2019
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-018-03057-z

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